Articular cartilage functions as a load-bearing tissue that is regulated by its mechanical environment. Although the effects of mechanical forces on articular cartilage are well-described, the molecular mechanisms responsible for these effects are not clear. The goal of these studies is to elucidate intracellular signal transduction pathways that mediate the biological effects of loading on cartilage. These studies will focus on the following four related specific aims. 1. Test the hypothesis that static and dynamic compressive loads influence distinct signal transduction pathways in articular chondrocytes. 2. Test the hypothesis that integrin-initiated and growth factor receptor-initiated pathways contribute to the response of articular chondrocytes to compressive loads. 3. Identify the specific signal transduction elements that are regulated by mechanical compression in articular chondrocytes. 4. Test the hypothesis that some aged cartilage possesses a defect in signal transduction that is manifested in its response to mechanical compression. These studies will conducted using bovine and human articular cartilage explant and gel suspension culture systems, focusing on proximal (membrane and cytoplasmic) events that mediate cell responses to extracellular signals. The demonstration by these studies that mechanical factors activate specific signal transduction pathways would not only lend insight into the molecular mechanisms that govern normal articular cartilage homeostasis, but would serve as a basis for investigating pathways whose disruption may contribute to cartilage disease.